Androgen ablation, the main form of therapy for metastatic prostate cancer, can produce significant palliation of symptoms in a majority of patients. The success of this approach depends on the ability of the prostate cancer cells to respond to androgens (and hence, be controlled by androgen antagonists). However, after a variable period of time, in virtually all instances the cancer cells become resistant to androgens and therapeutic anti-androgenic agents. As a result, patients become refractory to therapy and experience a rapid disease progression and death (Gittes, 1991, N. Engl. J. Med. 324: 236-245; Crawford et al., 1995, J. Clin. Endocrinol. Metabolism 80: 1062-1078). Despite intense investigation, the molecular basis for malignant transformation of prostatic epithelial cells and their transition to androgen resistance is still poorly understood (Lalani et al., 1997, Semin. Cancer Biol. 8: 53-9; Isaacs, et al., 1999, Urol Clin. North Am. 26: 263-73).
A search for genes differentially expressed in androgen dependent and independent prostatic carcinoma cells has been an avenue extensively investigated. During the past few years several novel genes like NPG-1 (Yang et al., 1998, Cancer Res. 58: 3732-3735), JC19, GC79 (Chang et al., 1997, Cancer Res. 57:4075-4081) and others (Blok et al., 1995, Prostate 26: 213-224; Chuaqui et al., 1997, Urology 50: 302-307; Geck et al., 1997, J. Steroid Mol. Biol. 63: 211-218) have been shown to be differentially expressed in androgen sensitive prostate cancer cells in comparison with the hormone refractory tumors. In addition, known genes like vimentin (Bussemarkers et al., 1992, Biochem. Biophys. Res. Commun. 182: 1254-1259), fibronectin (Schalken et al., 1988, Cancer Res. 48: 2042-2046), epithelial tropomyosin and cytochrome c oxidase (Wang et al., 1996, Cancer Res. 56: 3634-3637), the ETS-2 and SEF-2 factors (Liu et al., 1997, Prostate 30: 145-153) and PTI-1 gene (Sun et al., 1997, Cancer Res. 57: 18-23) have been found to be expressed at different levels in hormone sensitive and resistant prostate cancers. The role of these genes in malignant transformation and the transition to androgen resistance is not yet established.
Using a modified representational difference analysis (RDA) (Lisitsyn et al., 1993, Science 259: 946-951) six differentially expressed genes have been isolated from LNCaP-OM, an androgen resistant subline developed from the original LNCaP line (Platica et al., 1997, In Vitro Cellular and Developmental Biology, (Animal) 33: 147-149).
The present invention relates to the isolation, complete sequencing and characterization of one of these genes, termed “PAR” for “Prostatic Androgen Regulated”, and to the discovery that PAR expression is associated with malignant transformation. The National Institute of Genetics in Japan has reported that on Oct. 9, 1998, a nucleic acid sequence deposited by Hatakeyama et al. as accession number AB016492, “hjTB, a novel membrane protein at 1q21 rearranged in a jumping translocation”, was released by the DNA Data Bank of Japan (“DDBJ”). This sequence is 98% homologous to a substantial portion of the nucleotide sequence of PAR cDNA set forth in FIG. 2 and SEQ ID NO:1, but no other information regarding the gene was provided by Hatakeyama et al.